Oseltamivir phosphate is (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phosphate ula (I) which is
disclosed by J. C. Rohloffet al, J. Org. Chem. 1998 63: 4545-4550 and WO 98/07685 has a potent inhibitory activity against virus neuraminidase and is useful for prevention and/or treatment of influenza virus infections. It is the active ingredient of Tamiflu (Registered Trade Mark).
Crystalline form A of the compound of formula I, is characterized by an X ray powder diffraction pattern comprising at least three, preferably five, more preferably seven X-ray diffraction peaks (expressed in degrees 2θ (degrees 2-theta)) selected from the group consisting of approximately 5.1, approximately 12.4, approximately 13.0, approximately 14.3, approximately 15.2, approximately 16.1, approximately 19.0, approximately 19.3, approximately 20.3, approximately 20.6, approximately 21.6, approximately 24.4 and approximately 26.3.
A single crystal structural analysis of form A was conducted. Table 1 lists the crystal structure data. The experimental X-ray powder diffraction (XRPD) pattern collected with the form A corresponds to the theoretical pattern calculated from crystal structure data. The absolute configuration of the molecules was determined from single crystal structure data. The crystal packing of form A shows hydrogen bonds of the protonated amino group to three phosphate molecules. The amide oxygen accepts a hydrogen from another phosphate molecule. Consequently, the phosphate molecule forms hydrogen bonds to four different molecules of the active molecule. This results a hydrogen bonding pattern of tightly bond columns parallel to the crystallographic c-axis. A thermal ellipsoid plot of the crystal structure is shown in FIG. 8.
TABLE 1Crystal structure data of form AformAcrystal systemorthorhombicspace groupP 2(1) 2(1) 2crystal habitneedleunit cell dimensionsa = 23.8 Åb = 24.4 Åc = 7.4 Åα, β, γ = 90.0°temperature89° Kcell volume4289 Å3molecules in unit cell8calculated density1.27 g/cm3
For single crystal structure analysis a single crystal was mounted in a loop on a goniometer and measured at ambient conditions. Alternatively, the crystal was cooled in a nitrogen stream during measurement. Data were collected on a STOE Imaging Plate Diffraction System (IPDS) from STOE (Darmstadt). In this case Mo-radiation of 0.71 Å wavelength was used for data collection. Data was processed with STOE IPDS-software. The crystal structure was solved and refined with the ShelXTL program from Bruker AXS (Karlsruhe).
Alternatively, synchrotron radiation was used for data collection. A single crystal was mounted in a loop and cooled to 100 K in a nitrogen stream. Data was collected at the Swiss Light Source beamline XIOSA using a MAR CCD225 detector with synchrotron radiation and data processed with the program XDS. The crystal structure was solved and refined with the ShelXTL program from Bruker AXS (Karlsruhe).
The active pharmaceutical ingredient of the commercially available medicament Tamiflu is in crystalline form A.